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K. M. Madyastha - One of the best experts on this subject based on the ideXlab platform.
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Stereoselective hydroxylation of 4-methyl-2-cyclohexenone in rats: its relevance to R-(+)-Pulegone-mediated hepatotoxicity
Biochemical and Biophysical Research Communications, 2002Co-Authors: K. M. MadyasthaAbstract:R-(+)-Pulegone, a monoterpene ketone, is a potent hepatotoxin. One of the major metabolites of Pulegone has been shown to be p-cresol, a glutathione depletor and a known toxin. Allylic hydroxylation of 4-methyl-2-cyclohexenone results in the formation of p-cresol. The present study documents for the first time the involvement of cytochrome P-450 system and the stereochemical preference in this hydroxylation reaction. Incubation of PB-induced rat liver microsomes as well as reconstituted PB-induced cytochrome P-450 system with $\pm4-methyl-2-cyclohexenone$ in the presence of NADPH and $O_2$ resulted in the formation of 4-hydroxy-4-methyl-2-cyclohexenone and p-cresol. From the assay mixture, the unreacted substrate, viz., 4-methyl-2-cyclohexenone was isolated and purified and its optical rotation was found to be 2.2 (in $CHCl_3$). The observed enantiomeric excess in the recovered substrate was further confirmed by circular dichroism (CD) studies. The CD spectrum has a peak at 292 nm and a trough at 270 nm. The enantiomeric excess in the recovered substrate indicates that the hydroxylation at C-4 position is stereoselective. The significance of these results with respect to Pulegone-mediated hepatotoxicity is discussed.
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stereoselective hydroxylation of 4 methyl 2 cyclohexenone in rats its relevance to r Pulegone mediated hepatotoxicity
Biochemical and Biophysical Research Communications, 2002Co-Authors: K. M. MadyasthaAbstract:R-(+)-Pulegone, a monoterpene ketone, is a potent hepatotoxin. One of the major metabolites of Pulegone has been shown to be p-cresol, a glutathione depletor and a known toxin. Allylic hydroxylation of 4-methyl-2-cyclohexenone results in the formation of p-cresol. The present study documents for the first time the involvement of cytochrome P-450 system and the stereochemical preference in this hydroxylation reaction. Incubation of PB-induced rat liver microsomes as well as reconstituted PB-induced cytochrome P-450 system with $\pm4-methyl-2-cyclohexenone$ in the presence of NADPH and $O_2$ resulted in the formation of 4-hydroxy-4-methyl-2-cyclohexenone and p-cresol. From the assay mixture, the unreacted substrate, viz., 4-methyl-2-cyclohexenone was isolated and purified and its optical rotation was found to be 2.2 (in $CHCl_3$). The observed enantiomeric excess in the recovered substrate was further confirmed by circular dichroism (CD) studies. The CD spectrum has a peak at 292 nm and a trough at 270 nm. The enantiomeric excess in the recovered substrate indicates that the hydroxylation at C-4 position is stereoselective. The significance of these results with respect to Pulegone-mediated hepatotoxicity is discussed.
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transformation of a monoterpene ketone r Pulegone a potent hepatotoxin in mucor piriformis
Journal of Agricultural and Food Chemistry, 1999Co-Authors: K. M. Madyastha, H V ThulasiramAbstract:Biotransformation of a monoterpene ketone, (R)-(+)-Pulegone (I), a potent hepatotoxin, was studied using a fungal strain, Mucor piriformis. Eight metabolites, namely, 5-hydroxyPulegone (II), piperitenone (III), 6-hydroxyPulegone (IV), 3-hydroxyPulegone (V), 5-methyl-2-(1-hydroxy-1-methylethyl)-2-cyclohexene-1-one (VI), 3-hydroxyisoPulegone (VII), 7-hydroxypiperitenone (VIII), and 7-hydroxyPulegone (IX), have been isolated from the fermentation medium and identified. GC analysis of the metabolites indicated that II was the major metabolite formed. The organism initiates transformation either by hydroxylation at the C-5 position or by hydroxylation of the ring methylenes, the former being the major activity. On the basis of the identification of the metabolites, pathways for the biotransformation of (R)-(+)-Pulegone have been proposed. The mode of transformation of (S)-(-)-Pulegone by this organism was shown to be similar to that of its (R)-(+)-enantiomer. When isoPulegone (X) was used as the substrate, the organism isomerized it to Pulegone (I), which was then transformed to metabolites II-IX.
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hepatoprotective effect of c phycocyanin protection for carbon tetrachloride and r Pulegone mediated hepatotoxicty in rats
Biochemical and Biophysical Research Communications, 1998Co-Authors: Bhat B. Vadiraja, Nilesh W. Gaikwad, K. M. MadyasthaAbstract:Effect of C-phycocyanin (from Spirulina platensis) pretreatment on carbontetrachloride and R-(+)-Pulegone-induced hepatotoxicity in rats was studied, Intraperitoneal (i.p.) administration (200 mg/kg) of a single dose of phycocyanin to rats, one or three hours prior to R-(+)-Pulegone (250 mg/kg) or carbontetrachloride (0.6 ml/kg) challenge, significantly reduced the hepatotoxicity caused by these chemicals. For instance, serum glutamate pyruvate transaminase (SGPT) activity was almost equal to control values. The losses of microsomal cytochrome P450, glucose-6-phosphatase and aminopyrine-N-demethylase were significantly reduced, suggesting that phycocyanin provides protection to liver enzymes, It was noticed that the level of menthofuran, the proximate toxin of R-(+)-Pulegone was nearly 70% more in the urine samples collected from rats treated with R-(+)-Pulegone alone than rats treated with the combination of phycocyanin and R-(+)-Pulegone. The possible mechanism involved in the hepatoprotection is discussed.
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20Hepatoprotective effect of C-phycocyanin: Protection for carbon tetrachloride and R-(+)-Pulegone-mediated hepatotoxicty in rats
Biochemical and Biophysical Research Communications, 1998Co-Authors: Bhat B. Vadiraja, Nilesh W. Gaikwad, K. M. MadyasthaAbstract:Effect of C-phycocyanin (from Spirulina platensis) pretreatment on carbontetrachloride and R-(+)-Pulegone-induced hepatotoxicity in rats was studied. Intraperitoneal (i.p.) administration (200 mg/kg) of a single dose of phycocyanin to rats, one or three hours prior to R-(+)-Pulegone (250 mg/kg) or carbontetrachloride (0.6 ml/kg) challenge, significantly reduced the hepatotoxicity caused by these chemicals. For instance, serum glutamate pyruvate transaminase (SGPT) activity was almost equal to control values. The losses of microsomal cytochrome P450, glucose-6-phosphatase and aminopyrine-N-demethylase were significantly reduced, suggesting that phycocyanin provides protection to liver enzymes. It was noticed that the level of menthofuran, the proximate toxin of R-(+)-Pulegone was nearly 70% more in the urine samples collected from rats treated with R-(+)-Pulegone alone than rats treated with the combination of phycocyanin and R-(+)-Pulegone. The possible mechanism involved in the hepatoprotection is discussed.
Stephen V Frye - One of the best experts on this subject based on the ideXlab platform.
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chiral 1 3 oxathiane from Pulegone hexahydro 4 4 7 trimethyl 4h 1 3 benzoxathiin
Organic Syntheses, 2003Co-Authors: Ernest L Eliel, Joseph E Lynch, Fumitaka Kume, Stephen V FryeAbstract:Chiral 1,3-oxathiane from (+)-Pulegone: Hexahydro-4,4,7-trimethyl-4H-1,3-benzoxathiin intermediate: cis- and trans-5-Methyl-2-[1-methyl-1-(phenylmethylthio)ethyl]cyclohexanone reactant: 202.0 g (1.33 mol) of (+)-Pulegone intermediate: 2-(1-Mercapto-1-methylethyl)-5-methylcyclohexanol product: Hexahydro-4,4,7-trimethyl-4H-1,3-benzoxathiin. Keywords: addition, to CC; annulation, heterocyclic-[6]; cyclization, condensation; reduction, CO CHOH; reduction, miscellaneous; reduction, miscellaneous; mercaptans, stench; apparatus, for condensing liquid ammonia
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Organic Syntheses - Chiral 1,3‐Oxathiane from (+)‐Pulegone: Hexahydro‐4,4,7‐trimethyl‐4H‐1,3‐benzoxathiin
Organic Syntheses, 2003Co-Authors: Ernest L Eliel, Joseph E Lynch, Fumitaka Kume, Stephen V FryeAbstract:Chiral 1,3-oxathiane from (+)-Pulegone: Hexahydro-4,4,7-trimethyl-4H-1,3-benzoxathiin intermediate: cis- and trans-5-Methyl-2-[1-methyl-1-(phenylmethylthio)ethyl]cyclohexanone reactant: 202.0 g (1.33 mol) of (+)-Pulegone intermediate: 2-(1-Mercapto-1-methylethyl)-5-methylcyclohexanol product: Hexahydro-4,4,7-trimethyl-4H-1,3-benzoxathiin. Keywords: addition, to CC; annulation, heterocyclic-[6]; cyclization, condensation; reduction, CO CHOH; reduction, miscellaneous; reduction, miscellaneous; mercaptans, stench; apparatus, for condensing liquid ammonia
Sidney D Nelson - One of the best experts on this subject based on the ideXlab platform.
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metabolism of r Pulegone and r menthofuran by human liver cytochrome p 450s evidence for formation of a furan epoxide
Drug Metabolism and Disposition, 1999Co-Authors: Siamak C Khojastehbakht, Weiqiao Chen, Luke L Koenigs, Raimund M Peter, Sidney D NelsonAbstract:( R )-(+)-Pulegone, a monoterpene constituent of pennyroyal oil, is a hepatotoxin that has been used in folklore medicine as an abortifacient despite its potential lethal effects. Pulegone is metabolized by human liver cytochrome P-450s to menthofuran, a proximate hepatotoxic metabolite of Pulegone. Expressed human liver cytochrome (CYP) P-450s (1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4) were tested for their ability to catalyze the oxidations of Pulegone and menthofuran. Expressed CYP2E1, CYP1A2, and CYP2C19 oxidized Pulegone to menthofuran, with respective K m and V max values of 29 μM and 8.4 nmol/min/nmol P-450 for CYP2E1, 94 μM and 2.4 nmol/min/nmol P-450 for CYP1A2, and 31 μM and 1.5 nmol/min/nmol P-450 for CYP2C19. The human liver P-450s involved in the metabolism of menthofuran are the same as Pulegone except for the addition of CYP2A6. These P-450s were found to oxidize menthofuran to a newly identified metabolite, 2-hydroxymenthofuran, which is an intermediate in the formation of the known metabolites mintlactone and isomintlactone. Based on studies with 18 O 2 and H 2 18 O, 2-hydroxymenthofuran arises predominantly from a dihydrodiol formed from a furan epoxide. CYP2E1, CYP1A2, and CYP2C19 oxidized menthofuran with respective K m and V max values of 33 μM and 0.43 nmol/min/nmol P-450 for CYP2E1, 57 μM and 0.29 nmol/min/nmol P-450 for CYP1A2, and 62 μM and 0.26 nmol/min/nmol P-450 for CYP2C19.
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Metabolism of (R)-(+)-Pulegone and (R)-(+)-Menthofuran by Human Liver Cytochrome P-450s: Evidence for Formation of a Furan Epoxide
Drug Metabolism and Disposition, 1999Co-Authors: Siamak C. Khojasteh-bakht, Luke L Koenigs, Weiqiao Chen, Raimund M Peter, Sidney D NelsonAbstract:( R )-(+)-Pulegone, a monoterpene constituent of pennyroyal oil, is a hepatotoxin that has been used in folklore medicine as an abortifacient despite its potential lethal effects. Pulegone is metabolized by human liver cytochrome P-450s to menthofuran, a proximate hepatotoxic metabolite of Pulegone. Expressed human liver cytochrome (CYP) P-450s (1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4) were tested for their ability to catalyze the oxidations of Pulegone and menthofuran. Expressed CYP2E1, CYP1A2, and CYP2C19 oxidized Pulegone to menthofuran, with respective K m and V max values of 29 μM and 8.4 nmol/min/nmol P-450 for CYP2E1, 94 μM and 2.4 nmol/min/nmol P-450 for CYP1A2, and 31 μM and 1.5 nmol/min/nmol P-450 for CYP2C19. The human liver P-450s involved in the metabolism of menthofuran are the same as Pulegone except for the addition of CYP2A6. These P-450s were found to oxidize menthofuran to a newly identified metabolite, 2-hydroxymenthofuran, which is an intermediate in the formation of the known metabolites mintlactone and isomintlactone. Based on studies with 18 O 2 and H 2 18 O, 2-hydroxymenthofuran arises predominantly from a dihydrodiol formed from a furan epoxide. CYP2E1, CYP1A2, and CYP2C19 oxidized menthofuran with respective K m and V max values of 33 μM and 0.43 nmol/min/nmol P-450 for CYP2E1, 57 μM and 0.29 nmol/min/nmol P-450 for CYP1A2, and 62 μM and 0.26 nmol/min/nmol P-450 for CYP2C19.
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Investigations of mechanisms of reactive metabolite formation from (R)-(+)-Pulegone
Xenobiotica, 1992Co-Authors: Sidney D Nelson, D Thomassen, R H Mcclanahan, W. Perry Gordon, Norbert KnebelAbstract:1. (R)-(+)-Pulegone is a monoterpene that is oxidized by cytochromes P-450 to reactive metabolites that initiate events in the pathogenesis of hepatotoxicity in mice, rats and humans.2. Selective labelling of (R)-(+)-Pulegone with deuterium revealed that menthofuran was a proximate hepatotoxic metabolite formed by oxidation of the allylic methyl groups of Pulegone. Incubations of Pulegone with mouse liver microsomes in an atmosphere of 18O2 resulted in the formation of menthofuran that contained only oxygen-18 in the furan moiety. These results are consistent with oxidation of Pulegone to an allylic alcohol that reacts intramolecularly with the ketone moiety to form a hemiketal that subsequently dehydrates to generate menthofuran.3. Studies on the metabolism of menthofuran revealed that it is oxidized by cytochromes P-450 to an electrophilic γ-ketoenal that reacts with nucleophilic groups on proteins to form covalent adducts. In addition, diastereomeric mintlactones are formed. Investigations with H218O a...
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investigations of mechanisms of reactive metabolite formation from r Pulegone
Xenobiotica, 1992Co-Authors: Sidney D Nelson, D Thomassen, R H Mcclanahan, Perry W Gordon, Norbert KnebelAbstract:1. (R)-(+)-Pulegone is a monoterpene that is oxidized by cytochromes P-450 to reactive metabolites that initiate events in the pathogenesis of hepatotoxicity in mice, rats and humans.2. Selective labelling of (R)-(+)-Pulegone with deuterium revealed that menthofuran was a proximate hepatotoxic metabolite formed by oxidation of the allylic methyl groups of Pulegone. Incubations of Pulegone with mouse liver microsomes in an atmosphere of 18O2 resulted in the formation of menthofuran that contained only oxygen-18 in the furan moiety. These results are consistent with oxidation of Pulegone to an allylic alcohol that reacts intramolecularly with the ketone moiety to form a hemiketal that subsequently dehydrates to generate menthofuran.3. Studies on the metabolism of menthofuran revealed that it is oxidized by cytochromes P-450 to an electrophilic γ-ketoenal that reacts with nucleophilic groups on proteins to form covalent adducts. In addition, diastereomeric mintlactones are formed. Investigations with H218O a...
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partial characterization of biliary metabolites of Pulegone by tandem mass spectrometry detection of glucuronide glutathione and glutathionyl glucuronide conjugates
Drug Metabolism and Disposition, 1991Co-Authors: D Thomassen, John T Slattery, Paul G Pearson, Sidney D NelsonAbstract:The hepatotoxic monoterpene Pulegone is a major constituent of the herbal abortifacient pennyroyal oil. An approximately equimolar mixture of 2H3- and 14C-labeled Pulegone was administered to rats to study its phase II metabolism. Radioactive conjugates that were excreted into the bile were isolated by selective derivatization and HPLC separation, and subsequently characterized from the daughter ion mass spectra of protio- and deutero-analogs of each metabolite. The biliary metabolites characterized were glucuronide and glutathione (GSH) conjugates, accounting for approximately 3% of the radioactivity excreted in bile. The glucuronides, which were 2-fold more abundant than GSH conjugates, were mainly of hydroxylated Pulegone and hydroxylated, reduced Pulegone. The three GSH conjugates contained xenobiotic moieties that varied in their oxidation state; one of these was tentatively identified as the GSH conjugate of the proximate oxygenated metabolite, menthofuran. The two other GSH conjugates apparently underwent subsequent glucuronidation since novel glutathionyl glucuronide conjugates were identified that contained nonhydroxylated xenobiotic moieties. The results indicate that Pulegone is bioactivated via at least three distinct pathways, each marked by a different GSH conjugate. Characterization of these conjugates represents a first step in the identification of the reactive metabolites from which they are derived.
Ernest L Eliel - One of the best experts on this subject based on the ideXlab platform.
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chiral 1 3 oxathiane from Pulegone hexahydro 4 4 7 trimethyl 4h 1 3 benzoxathiin
Organic Syntheses, 2003Co-Authors: Ernest L Eliel, Joseph E Lynch, Fumitaka Kume, Stephen V FryeAbstract:Chiral 1,3-oxathiane from (+)-Pulegone: Hexahydro-4,4,7-trimethyl-4H-1,3-benzoxathiin intermediate: cis- and trans-5-Methyl-2-[1-methyl-1-(phenylmethylthio)ethyl]cyclohexanone reactant: 202.0 g (1.33 mol) of (+)-Pulegone intermediate: 2-(1-Mercapto-1-methylethyl)-5-methylcyclohexanol product: Hexahydro-4,4,7-trimethyl-4H-1,3-benzoxathiin. Keywords: addition, to CC; annulation, heterocyclic-[6]; cyclization, condensation; reduction, CO CHOH; reduction, miscellaneous; reduction, miscellaneous; mercaptans, stench; apparatus, for condensing liquid ammonia
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Organic Syntheses - Chiral 1,3‐Oxathiane from (+)‐Pulegone: Hexahydro‐4,4,7‐trimethyl‐4H‐1,3‐benzoxathiin
Organic Syntheses, 2003Co-Authors: Ernest L Eliel, Joseph E Lynch, Fumitaka Kume, Stephen V FryeAbstract:Chiral 1,3-oxathiane from (+)-Pulegone: Hexahydro-4,4,7-trimethyl-4H-1,3-benzoxathiin intermediate: cis- and trans-5-Methyl-2-[1-methyl-1-(phenylmethylthio)ethyl]cyclohexanone reactant: 202.0 g (1.33 mol) of (+)-Pulegone intermediate: 2-(1-Mercapto-1-methylethyl)-5-methylcyclohexanol product: Hexahydro-4,4,7-trimethyl-4H-1,3-benzoxathiin. Keywords: addition, to CC; annulation, heterocyclic-[6]; cyclization, condensation; reduction, CO CHOH; reduction, miscellaneous; reduction, miscellaneous; mercaptans, stench; apparatus, for condensing liquid ammonia
Joseph E Lynch - One of the best experts on this subject based on the ideXlab platform.
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chiral 1 3 oxathiane from Pulegone hexahydro 4 4 7 trimethyl 4h 1 3 benzoxathiin
Organic Syntheses, 2003Co-Authors: Ernest L Eliel, Joseph E Lynch, Fumitaka Kume, Stephen V FryeAbstract:Chiral 1,3-oxathiane from (+)-Pulegone: Hexahydro-4,4,7-trimethyl-4H-1,3-benzoxathiin intermediate: cis- and trans-5-Methyl-2-[1-methyl-1-(phenylmethylthio)ethyl]cyclohexanone reactant: 202.0 g (1.33 mol) of (+)-Pulegone intermediate: 2-(1-Mercapto-1-methylethyl)-5-methylcyclohexanol product: Hexahydro-4,4,7-trimethyl-4H-1,3-benzoxathiin. Keywords: addition, to CC; annulation, heterocyclic-[6]; cyclization, condensation; reduction, CO CHOH; reduction, miscellaneous; reduction, miscellaneous; mercaptans, stench; apparatus, for condensing liquid ammonia
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Organic Syntheses - Chiral 1,3‐Oxathiane from (+)‐Pulegone: Hexahydro‐4,4,7‐trimethyl‐4H‐1,3‐benzoxathiin
Organic Syntheses, 2003Co-Authors: Ernest L Eliel, Joseph E Lynch, Fumitaka Kume, Stephen V FryeAbstract:Chiral 1,3-oxathiane from (+)-Pulegone: Hexahydro-4,4,7-trimethyl-4H-1,3-benzoxathiin intermediate: cis- and trans-5-Methyl-2-[1-methyl-1-(phenylmethylthio)ethyl]cyclohexanone reactant: 202.0 g (1.33 mol) of (+)-Pulegone intermediate: 2-(1-Mercapto-1-methylethyl)-5-methylcyclohexanol product: Hexahydro-4,4,7-trimethyl-4H-1,3-benzoxathiin. Keywords: addition, to CC; annulation, heterocyclic-[6]; cyclization, condensation; reduction, CO CHOH; reduction, miscellaneous; reduction, miscellaneous; mercaptans, stench; apparatus, for condensing liquid ammonia
